EP2582394B1 - Stabilised human immunoglobulin composition - Google Patents
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- EP2582394B1 EP2582394B1 EP11735499.3A EP11735499A EP2582394B1 EP 2582394 B1 EP2582394 B1 EP 2582394B1 EP 11735499 A EP11735499 A EP 11735499A EP 2582394 B1 EP2582394 B1 EP 2582394B1
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39591—Stabilisation, fragmentation
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- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
Definitions
- the invention relates to the formulation of human immunoglobulin G, useful in therapy.
- IgG immunoglobulin G
- examples include primitive immune deficiencies with defective antibody production, Kawasaki disease, immunologic thrombocytopenic purpura in children and adults, secondary immune deficiencies with defective antibody production, in particular chronic lymphocytic leukemia or myeloma associated with recurrent infections, childhood HIV infection associated with bacterial infections, multifocal motor neuropathies, Guillain-Barré syndrome, severe acute or chronic parvovirus B19 infections Acquired or constitutional immunodeficiency, corticosteroid dermatomyositis, acute myasthenia, idiopathic chronic polyradiculoneuropathy, immune thrombocytopenic purpura, for example associated with HIV infection, stiff man syndrome (Stiffman syndrome) , autoimmune neutropenia, resistant autoimmune erythroblastopenia, anti-coagulati acquired by autoantibodies, rheumatoid arthritis, etc.
- Stiffman syndrome autoimmune neutropenia
- resistant autoimmune erythroblastopenia anti-
- IgGIV intravenous IgG injectable compositions
- IgGIV it is known that it is necessary to stabilize IgGIV to avoid in particular the formation of aggregates (oligomers and polymers) capable of activating the complement system with associated risks of anaphylactic reactions, headaches, fevers, redness, voltage drop ( Bolli et al, Biologicals, 2010, 38: 150-157 ).
- aggregates oligomers and polymers
- the presence of dimers in IgGIV has been correlated with decreases in blood pressure in vivo.
- Other physicochemical degradations may also occur during the storage of IgG such as, among others, oxidation and hydrolysis.
- the stabilization of IgG therefore requires the addition of compounds, conventionally chosen from sugars and amino acids, in order to obtain not only non-IgG compositions. degraded suitable for therapeutic use but also IgG compositions having increased stability during storage.
- Lyophilized IgGIV compositions are commercially available, for example under the trade names Polygam TM (American Red Cross), Gammar IV TM (Armor Pharmaceutical Company) and Venoglobulin TM I (Alpha) containing as stabilizers 2% glucose. , 5% sucrose and 2% D-mannitol respectively.
- Liquid compositions of IgGIV which contain 10% maltose as stabilizers, 0.16 to 0.24 M glycine and 5% D-sorbitol are respectively known under the trade names Octagam TM, (Octapharma). , Gamunex TM 10% (Talecris) and Venoglobulin TM (Alpha).
- the Applicant has now developed a pharmaceutical composition
- a pharmaceutical composition comprising human immunoglobulin G formulated with glycine and a nonionic detergent, at a pH lower than or equal to 4.8.
- the inventors have more particularly shown the importance of a low pH to stabilize this formulation.
- An object of the invention is therefore a pharmaceutical composition comprising human immunoglobulin G (IgG), according to claim 1.
- IgG immunoglobulin G
- composition according to the invention is advantageously in liquid form. It can be prepared directly or be obtained by reconstitution with water from a lyophilisate.
- Another object of the invention is a solid composition obtained by desiccating, preferably lyophilizing, a liquid composition as defined herein.
- human immunoglobulin G or "human IgG” in the context of the invention means polyvalent immunoglobulins which are essentially IgGs, possibly including IgMs. It may be whole immunoglobulins, or fragments such as F (ab ') 2 or F (ab) and any intermediate fraction obtained during the process of manufacturing polyvalent immunoglobulins.
- Stability corresponds to the physical and / or chemical stability of IgG.
- physical stability refers to the reduction or absence of formation of insoluble or soluble aggregates of the dimeric, oligomeric or polymeric forms of Ig, as well as the reduction or absence of any structural denaturation of the molecule. .
- chemical stability refers to the reduction or absence of any chemical modification of IgG during storage, in the solid state or in dissolved form, under accelerated conditions. For example, the phenomena of hydrolysis, deamination, and / or oxidation are avoided or delayed. The oxidation of sulfur-containing amino acids is limited.
- the concentration of IgG is 100 g / l.
- concentrations are determined with respect to the compositions in liquid form, before drying, or after reconstitution as an injectable preparation.
- composition does not contain mannitol. Indeed, it has been shown that mannitol is not essential for the stabilization of the formulation.
- the only excipients are glycine and nonionic detergent.
- the nonionic detergent used in the composition according to the invention is polysorbate 80 (or Tween®80 which is polyoxyethylene sorbitan monooleate).
- compositions of the invention may also comprise other additives.
- Such an additive may also represent a compound chosen from among the different categories of stabilizers conventionally used in the technical field of the invention, such as surfactants, sugars and amino acids, than an excipient added to the formulation in order to adjust, for example, pH, ionic strength, etc.
- the composition according to the invention does not comprise other excipients than said glycine and nonionic detergent.
- Such a composition has the advantage of offering a good stabilization of the immunoglobulin compositions and a reduction of the times and costs of preparation on an industrial scale thanks to the presence of a minimal effective number of excipients as well as the presence a minimum effective amount of excipients.
- Immunoglobulin G is generally obtained by fractionation of human blood plasma and presented in an aqueous medium.
- the aqueous medium is composed of water for injection (PPI water) which may contain pharmaceutically acceptable excipients and compatible with IgG.
- the IgG compositions may previously undergo specific virus inactivation / removal steps, such as detergent solvent treatment, pasteurization and / or nanofiltration.
- the composition according to the invention comprises IgG which can be polyclonal or monoclonal. IgGs can be isolated from human or animal blood or produced by other means, for example by molecular biology techniques, for example in cell systems well known to those skilled in the art.
- the composition according to the invention is particularly suitable for highly purified IgG.
- the IgGs of the present invention are obtained by fractionation of human plasma.
- Preferred fractionation methods of human plasma are described by Cohn et al (J. Am Chem Soc., 68, 459, 1946 ) Kistler et al. (Vox Sang., 7, 1962, 414-424 ) Steinbuch et al (Rev. Fr. Etc. Clin and Biol., XIV, 1054, 1969 ) and in the patent application WO 94/9334 .
- a method for preparing an immunoglobulin G composition is also described in the patent application WO 02/092632 .
- the liquid compositions according to the invention can be desiccated to obtain a solid form which is preserved longer and is more convenient for transport and marketing. Desiccation is a method of removing water at a high stage. It is a dehydration to remove as much water as possible. This phenomenon can be natural or forced. This desiccation can be carried out using freeze-drying, atomization and cryoatomization techniques.
- the preferred mode of obtaining the solid form of the composition for pharmaceutical use according to the invention is lyophilization. Lyophilization methods are well known to those skilled in the art, see for example [ Wang et al, Lyophilization and development of solid protein pharmaceuticals, International Journal of Pharmaceutics, Vol 203, p 1-60, 2000 ].
- the degree of humidity is less than or equal to 3% by weight, preferably less than or equal to 2.5%, preferably less than or equal to 2%, preferably less than or equal to 1.5%.
- composition according to the invention may advantageously be subjected to a method of elimination or inactivation of the infectious agents, for example by dry heating of the lyophilizate.
- the solid composition according to the invention preferably in freeze-dried form, can be dissolved in water for injection (or "water for injection” or WFI), to obtain a formulation for therapeutic use.
- water for injection or "water for injection” or WFI
- composition of the invention is useful in therapy, and especially in injectable form, preferably intravenously.
- the composition is then in liquid form.
- the protein solution is composed of different subclasses of immunoglobulins (Ig1, Ig2, Ig3 and Ig4) which have a heterogeneity for their isoelectric point (pI), ranging from 5 to 9 approximately.
- the pH actually plays directly on the effective charge of immunoglobulins (Ig), for those with a low pI ( ⁇ 7.0). In this pH range, some Ig change from a generally positive charge to a generally negative charge, which changes the nature of electrostatic interactions with other Ig. The aggregation observed here after pH adjustment is similar to oligomerization.
- the Figure 2 illustrates the results of turbidity measurement monitoring (OD at 400nm) under heat stress conditions (57 ° C) showing the influence of pH on macroscopic Ig aggregation.
- pH of 4.6 is the most favorable, the rise in pH favoring aggregation phenomena.
- Rotative agitation stress (flask reversal) is also conducted to justify the role of pH on aggregation at the water-air interfaces. Turbidity measurements are performed after centrifugation and resuspension to remove any microbubbles. The Figure 3 shows that the aggregation of Ig at the interfaces is strongly influenced by the pH.
- the GT80 and GT20 formulations were prepared by diluting the Ig in formulation buffers to achieve a protein titre of 100g / l, and the concentrations referred to excipients. Hydrochloric acid was used to adjust the pH.
- Anti-complementary activity was determined by measuring the aspecific uptake of complement by Ig. This test describes the ability of immunoglobulins to activate the complement system, too strong activation of the complement may affect the tolerance of the product during its injection.
- the IgNG, GT80 and GT20 formulations generally gave the best results.
- the surfactant (Tween) promoted the physical stability of the formulations.
- the presence of mannitol was not essential, the GT80 and GT20 formulations (lacking mannitol) having stabilities at least as good as the formulation IgNG (with mannitol).
- GT80 and IgNG Formulations (10% Human IgG Immune Globulin) ⁇ / u> ⁇ /b> IGNG Glycine (93mM) - Mannitol (175mM- 32g / L) - Tween 80 50ppm GT80 Glycine (250mM) - Tween 80 50ppm
- the GT80 formulation consisting of Glycine (250 mM) and Tween 80 (50 ppm) is a stable formulation suitable for commercial therapeutic use. After 12 months at 25 ° C, all the analyzes performed are according to the European Pharmacopoeia.
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Description
L'invention a trait à la formulation d'immunoglobulines G humaines, utiles en thérapie.The invention relates to the formulation of human immunoglobulin G, useful in therapy.
De nombreuses pathologies sont actuellement traitées par des compositions d'immunoglobulines G (IgG). On peut citer par exemple les déficits immunitaires primitifs avec défaut de production d'anticorps, la maladie de Kawasaki, le purpura thrombopénique immunologique de l'enfant et de l'adulte, les déficits immunitaires secondaires avec défaut de production d'anticorps, en particulier la leucémie lymphoïde chronique ou myélome associés à des infections à répétition, l'infection de l'enfant par le VIH associé à des infections bactériennes, les neuropathies motrices multifocales, le syndrome de Guillain-Barré, les infections aiguës sévères ou chroniques à Parvovirus B19, l'immunodéficience acquise ou constitutionnelle, la dermatomyosite cortico-résistante, la myasthénie aiguë, la polyradiculonévrite chronique idiopathique, le purpura thrombopénique immunologique, par exemple associé à l'infection par le VIH, le syndrome de l'homme raide (Stiffman syndrome), la neutropénie auto-immune, l'erythroblastopénie auto-immune résistante, le syndrome d'anti-coagulation acquise par auto-anticorps, la polyarthrite rhumatoïde, etc.Many pathologies are currently treated with immunoglobulin G (IgG) compositions. Examples include primitive immune deficiencies with defective antibody production, Kawasaki disease, immunologic thrombocytopenic purpura in children and adults, secondary immune deficiencies with defective antibody production, in particular chronic lymphocytic leukemia or myeloma associated with recurrent infections, childhood HIV infection associated with bacterial infections, multifocal motor neuropathies, Guillain-Barré syndrome, severe acute or chronic parvovirus B19 infections Acquired or constitutional immunodeficiency, corticosteroid dermatomyositis, acute myasthenia, idiopathic chronic polyradiculoneuropathy, immune thrombocytopenic purpura, for example associated with HIV infection, stiff man syndrome (Stiffman syndrome) , autoimmune neutropenia, resistant autoimmune erythroblastopenia, anti-coagulati acquired by autoantibodies, rheumatoid arthritis, etc.
Au cours de ces dernières années, la très forte demande d'IgG a engendré des situations de tension extrêmes sur les approvisionnements, pouvant aller jusqu'à des situations de pénurie en Europe et aux Etats Unis d'Amérique.In recent years, the very high demand for IgG has led to situations of extreme tension on supplies, which can go as far as shortages in Europe and the United States of America.
Dans ce contexte, il y a un besoin grandissant de produire des compositions d'IgG, injectables par voie intraveineuse, à partir par exemple de plasmas humains. Avec l'essor de ces besoins en IgG, la stabilisation de ces compositions d'IgG injectables par voie intraveineuse (IgGIV) en vue de leur utilisation thérapeutique et de leur conservation revêt un caractère fondamental.In this context, there is a growing need to produce injectable intravenous IgG compositions from, for example, human plasmas. With the growth of these IgG requirements, the stabilization of these intravenous IgG injectable compositions (IgGIV) for therapeutic use and preservation has a fundamental character.
A cet égard, on sait qu'il est nécessaire de stabiliser les IgGIV pour éviter notamment la formation d'agrégats (oligomères et polymères) susceptibles d'activer le système du complément avec des risques associés de réactions anaphylactiques, céphalées, fièvres, rougeurs, baisse de tension (
La stabilisation des IgG nécessite donc l'ajout de composés, classiquement choisis parmi les sucres et les acides aminés, afin d'obtenir non seulement des compositions d'IgG non dégradées appropriées à un usage thérapeutique mais également des compositions d'IgG présentant une stabilité accrue durant le stockage.The stabilization of IgG therefore requires the addition of compounds, conventionally chosen from sugars and amino acids, in order to obtain not only non-IgG compositions. degraded suitable for therapeutic use but also IgG compositions having increased stability during storage.
Plusieurs formulations d'immunoglobulines humaines destinées à une administration intraveineuse ont été proposées (cf notamment le brevet
Des compositions d'IgGIV lyophilisées sont disponibles dans le commerce, par exemple sous les noms de marques Polygam™ (American Red Cross), Gammar IV™ (Armour Pharmaceutical Company) et Venoglobulin™I (Alpha) contenant comme stabilisants du glucose à 2%, du saccharose à 5% et du D-mannitol à 2% respectivement.Lyophilized IgGIV compositions are commercially available, for example under the trade names Polygam ™ (American Red Cross), Gammar IV ™ (Armor Pharmaceutical Company) and Venoglobulin ™ I (Alpha) containing as
Des compositions liquides d'IgGIV qui contiennent comme stabilisants du maltose à 10%, de la glycine de 0,16 à 0,24 M et du D-sorbitol à 5% sont respectivement connues sous les noms de marque Octagam™, (Octapharma), Gamunex™ 10% (Talecris) et Venoglobulin™ (Alpha).Liquid compositions of IgGIV which contain 10% maltose as stabilizers, 0.16 to 0.24 M glycine and 5% D-sorbitol are respectively known under the trade names Octagam ™, (Octapharma). , Gamunex ™ 10% (Talecris) and Venoglobulin ™ (Alpha).
Cependant il existe toujours un besoin en des formulations d'IgIV qui soient bien tolérées et qui soient suffisamment stables pour une conservation optimale, facilitant leur utilisation.However, there is still a need for IVIG formulations that are well tolerated and sufficiently stable for optimal preservation, facilitating their use.
La Demanderesse a maintenant mis au point une composition pharmaceutique comprenant des immunoglobulines G humaines formulées avec de la glycine et un détergent non ionique, à un pH inférieur ou égal à 4,8.The Applicant has now developed a pharmaceutical composition comprising human immunoglobulin G formulated with glycine and a nonionic detergent, at a pH lower than or equal to 4.8.
Les inventeurs ont plus particulièrement montré l'importance d'un faible pH pour stabiliser cette formulation.The inventors have more particularly shown the importance of a low pH to stabilize this formulation.
Un objet de l'invention est donc une composition pharmaceutique comprenant des immunoglobulines G humaines (IgG), conforme à la revendication 1.An object of the invention is therefore a pharmaceutical composition comprising human immunoglobulin G (IgG), according to
La composition présente un pH compris entre 4,4 et 4,8. De préférence le pH est de 4,6.The composition has a pH of between 4.4 and 4.8. Preferably the pH is 4.6.
La composition selon l'invention est avantageusement sous forme liquide. Elle peut être préparée directement ou être obtenue par reconstitution avec de l'eau, à partir d'un lyophilisat.The composition according to the invention is advantageously in liquid form. It can be prepared directly or be obtained by reconstitution with water from a lyophilisate.
Un autre objet de l'invention est une composition solide obtenue par dessication, de préférence lyophilisation, d'une composition liquide telle que définie ici.Another object of the invention is a solid composition obtained by desiccating, preferably lyophilizing, a liquid composition as defined herein.
On entend par « Immunoglobulines G humaines » ou « IgG humaines » dans le cadre de l'invention, des immunoglobulines polyvalentes qui sont essentiellement des IgG, incluant éventuellement des IgM. Il peut s'agir d'immunoglobulines entières, ou de fragments tels que F(ab')2 ou F(ab) et toute fraction intermédiaire obtenue au cours du procédé de fabrication des immunoglobulines polyvalentes.The term "human immunoglobulin G" or "human IgG" in the context of the invention means polyvalent immunoglobulins which are essentially IgGs, possibly including IgMs. It may be whole immunoglobulins, or fragments such as F (ab ') 2 or F (ab) and any intermediate fraction obtained during the process of manufacturing polyvalent immunoglobulins.
Le terme « stabilité » correspond à la stabilité physique et/ou chimique des IgG.The term "stability" corresponds to the physical and / or chemical stability of IgG.
Le terme « stabilité physique » se réfère à la réduction ou l'absence de formation d'agrégats insolubles ou solubles des formes dimériques, oligomériques ou polymériques des Ig, ainsi qu'à la réduction ou l'absence de toute dénaturation structurale de la molécule.The term "physical stability" refers to the reduction or absence of formation of insoluble or soluble aggregates of the dimeric, oligomeric or polymeric forms of Ig, as well as the reduction or absence of any structural denaturation of the molecule. .
Le terme "stabilité chimique" se réfère à la réduction ou l'absence de toute modification chimique des IgG pendant le stockage, à l'état solide ou sous forme dissoute, dans des conditions accélérées. Par exemple, les phénomènes d'hydrolyse, déamination, et/ou oxydation sont évités ou retardés. L'oxydation des acides aminés contenant du soufre est limitée.The term "chemical stability" refers to the reduction or absence of any chemical modification of IgG during storage, in the solid state or in dissolved form, under accelerated conditions. For example, the phenomena of hydrolysis, deamination, and / or oxidation are avoided or delayed. The oxidation of sulfur-containing amino acids is limited.
La concentration en IgG est de 100 g/l.The concentration of IgG is 100 g / l.
Les concentrations sont déterminées vis à vis des compositions sous forme liquide, avant dessication, ou après reconstitution sous forme de préparation injectable.The concentrations are determined with respect to the compositions in liquid form, before drying, or after reconstitution as an injectable preparation.
La composition ne contient pas de mannitol. En effet, il a été montré que le mannitol n'était pas essentiel à la stabilisation de la formulation.The composition does not contain mannitol. Indeed, it has been shown that mannitol is not essential for the stabilization of the formulation.
Plus particulièrement, dans un mode de réalisation préféré, les seuls excipients sont la glycine et le détergent non-ionique.More particularly, in a preferred embodiment, the only excipients are glycine and nonionic detergent.
Le détergent non ionique utilisé dans la composition selon l'invention est le polysorbate 80 (ou Tween®80 qui est du polyoxyéthylènesorbitanne-monooléate).The nonionic detergent used in the composition according to the invention is polysorbate 80 (or Tween®80 which is polyoxyethylene sorbitan monooleate).
Les compositions de l'invention peuvent aussi comprendre d'autres additifs. Un tel additif peut aussi bien représenter un composé choisi parmi les différentes catégories de stabilisants classiquement utilisés dans le domaine technique de l'invention, tels que les tensioactifs, les sucres et les acides aminés, qu'un excipient ajouté à la formulation afin d'en ajuster, par exemple, le pH, la force ionique etc. Alternativement, la composition selon l'invention ne comprend pas d'autres excipients que lesdits glycine et détergent non ionique. Une telle composition présente l'avantage d'offrir une bonne stabilisation des compositions d'immunoglobulines et une réduction des durées et des coûts de préparation à l'échelle industrielle grâce à la présence d'un nombre minimal efficace d'excipients ainsi que la présence d'une quantité minimale efficace d'excipients.The compositions of the invention may also comprise other additives. Such an additive may also represent a compound chosen from among the different categories of stabilizers conventionally used in the technical field of the invention, such as surfactants, sugars and amino acids, than an excipient added to the formulation in order to adjust, for example, pH, ionic strength, etc. Alternatively, the composition according to the invention does not comprise other excipients than said glycine and nonionic detergent. Such a composition has the advantage of offering a good stabilization of the immunoglobulin compositions and a reduction of the times and costs of preparation on an industrial scale thanks to the presence of a minimal effective number of excipients as well as the presence a minimum effective amount of excipients.
La composition selon l'invention comprend :
- 100 g/l d'IgG
- 250 mM de glycine
- 50 mg/l de
polysorbate 80.
- 100 g / l of IgG
- 250 mM glycine
- 50 mg / l of
polysorbate 80.
Les immunoglobulines G sont généralement obtenues par fractionnement du plasma sanguin humain, et présentées dans un milieu aqueux. Le milieu aqueux est composé d'eau pour préparation injectable (eau PPI) pouvant contenir des excipients pharmaceutiquement acceptables et compatibles avec les IgG. Les compositions d'IgG peuvent au préalable subir des étapes spécifiques d'inactivation/élimination de virus, tel qu'un traitement solvant détergent, une pasteurisation et/ou une nanofiltration. La composition selon l'invention comprend des IgG qui peuvent être polyclonales ou monoclonales. Les IgG peuvent être isolées à partir du sang humain ou animal ou produites par d'autres moyens, par exemple par des techniques de biologie moléculaire, par exemple dans des systèmes cellulaires bien connus de l'homme du métier. La composition selon l'invention est particulièrement adaptée aux IgG hautement purifiées. Avantageusement, les IgG de la présente invention sont obtenues par fractionnement du plasma humain. Des méthodes de fractionnement préférées du plasma humain sont décrites par
Les compositions liquides selon l'invention peuvent subir une dessiccation pour obtenir une forme solide qui se conserve plus longtemps et est plus pratique pour le transport et la commercialisation. La dessiccation est un procédé d'élimination de l'eau à un stade poussé. Il s'agit d'une déshydratation visant à éliminer autant d'eau que possible. Ce phénomène peut être naturel ou forcé. Cette dessiccation peut être réalisée à l'aide des techniques de lyophilisation, d'atomisation et de cryoatomisation. Le mode préféré d'obtention de la forme solide de la composition à usage pharmaceutique selon l'invention est la lyophilisation. Les méthodes de lyophilisation sont bien connues de l'homme du métier, voir par exemple [
La composition selon l'invention peut être avantageusement soumise à une méthode d'élimination ou d'inactivation des agents infectieux, par exemple par chauffage à sec du lyophilisat.The composition according to the invention may advantageously be subjected to a method of elimination or inactivation of the infectious agents, for example by dry heating of the lyophilizate.
La composition solide selon l'invention, de préférence sous forme lyophilisée, peut être dissoute dans de l'eau pour préparations injectables (ou « water for injection ou WFI »), pour obtenir une formulation à usage thérapeutique.The solid composition according to the invention, preferably in freeze-dried form, can be dissolved in water for injection (or "water for injection" or WFI), to obtain a formulation for therapeutic use.
La composition de l'invention est utile en thérapie, et notamment sous forme injectable, de préférence par voie intraveineuse. La composition est alors sous forme liquide.The composition of the invention is useful in therapy, and especially in injectable form, preferably intravenously. The composition is then in liquid form.
-
Les
Figures 1A et 1B représentent des histogrammes montrant les mesures de diffusion de la lumière en mode dynamique (Figure 1A ) ou en mode statique (Figure 1B ), sur des formulations d'immunoglobulines dans de la glycine, à diverses valeurs de pH.TheFigures 1A and 1B represent histograms showing dynamic light scattering measurements (Figure 1A ) or in static mode (Figure 1B ), on immunoglobulin formulations in glycine, at various pH values. -
La
Figure 2 est un graphe qui illustre les résultats d'un suivi de mesure de turbidité (DO à 400nm) de formulations d'immunoglobulines à divers pH, dans des conditions de stress thermique (57°C).TheFigure 2 is a graph that illustrates the results of turbidity measurement monitoring (OD at 400nm) of immunoglobulin formulations at various pH, under heat stress conditions (57 ° C). -
La
Figure 3 est un graphe qui illustre l'influence du pH sur la turbidité de formulations d'immunoglobulines, en conditions de stress d'agitation rotative (retournement des flacons).TheFigure 3 is a graph that illustrates the influence of pH on the turbidity of immunoglobulin formulations, under rotating agitation stress conditions (flask rollover).
L'influence du pH a été testée sur des formulations d'immunoglobulines G humaines concentrées à 10% dans un tampon glycine 100mM, le pH étant ajusté dans des conditions non dénaturantes, c'est-à-dire par dialyse contre un tampon ajusté en pH permettant d'atteindre le pH visé. Plusieurs pH sont testés : 4,6 ; 5,2 ; 5,7; 6,4 ; 6,8.The influence of pH was tested on 10% human immunoglobulin G formulations concentrated in 100mM glycine buffer, the pH being adjusted under non-denaturing conditions, i.e. by dialysis against an adjusted buffer. pH to reach the target pH. Several pHs are tested: 4.6; 5.2; 5.7; 6.4; 6.8.
L'état d'agrégation des immunoglobulines est suivi par un test de diffusion de la lumière (angle de 90°), après ajustement du pH (t=0). Après ajustement et sans appliquer de stress sur les formulations, les solutions présentent des états d'agrégation différents.The aggregation state of the immunoglobulins is followed by a light scattering test (90 ° angle) after pH adjustment (t = 0). After adjustment and without applying stress on the formulations, the solutions have different states of aggregation.
En effet, les mesures de diffusion de la lumière en mode statique et en mode dynamique montrent une augmentation de l'agrégation submicronique avec l'élévation du pH (
La solution protéique est composée de différentes sous-classes d'immunoglobulines (Ig1, Ig2, Ig3 et Ig4) qui présentent une hétérogénéité pour leur point isoélectrique (pI), allant de 5 à 9 environ. Le pH jouerait en fait directement sur la charge effective des immunoglobulines (Ig), pour celles qui ont un pI bas (<7,0). Dans cette zone de pH, certaines Ig passent d'une charge globalement positive à une charge globalement négative, ce qui change la nature des interactions électrostatiques avec les autres Ig. L'agrégation observée ici après ajustement du pH s'apparente à de l'oligomérisation.The protein solution is composed of different subclasses of immunoglobulins (Ig1, Ig2, Ig3 and Ig4) which have a heterogeneity for their isoelectric point (pI), ranging from 5 to 9 approximately. The pH actually plays directly on the effective charge of immunoglobulins (Ig), for those with a low pI (<7.0). In this pH range, some Ig change from a generally positive charge to a generally negative charge, which changes the nature of electrostatic interactions with other Ig. The aggregation observed here after pH adjustment is similar to oligomerization.
Les tests montrent que pour avoir des interactions globalement répulsives et donc stabilisantes, un pH d'environ 4,6 est favorable.The tests show that to have globally repulsive and therefore stabilizing interactions, a pH of about 4.6 is favorable.
La
Un stress d'agitation rotative (retournement des flacons) est aussi conduit pour justifier le rôle du pH sur l'agrégation aux interfaces eau-air. Des mesures de turbidité sont réalisées après centrifugation et remise en suspension pour éliminer les microbulles éventuelles. La
Plusieurs formulations d'immunoglobulines humaines à une concentration de 10% ont été préparées, avec les excipients suivants, à pH 4,6 :
Les immunoglobulines utilisées proviennent d'une solution concentrée à 168g/L à pH=4,7, sans aucun excipient de formulation, cette solution ayant été obtenue à partir d'un fractionnement de plasma humain, puis ultrafiltration tangentielle. Les formulations GT80 et GT20 ont été préparées par dilution des Ig dans des tampons de formulation pour atteindre un titre protéique de 100g/l, et les concentrations visées en excipients. De l'acide chlorhydrique a été utilisé pour ajuster le pH.The immunoglobulins used come from a solution concentrated at 168 g / L at pH = 4.7, without any formulation excipient, this solution having been obtained from a fractionation of human plasma and then tangential ultrafiltration. The GT80 and GT20 formulations were prepared by diluting the Ig in formulation buffers to achieve a protein titre of 100g / l, and the concentrations referred to excipients. Hydrochloric acid was used to adjust the pH.
Les formulations ont été soumises à des tests de stabilité dite « accélérée », en les conservant à 25°C ou à 40°C, pendant 6, 13 ou 19 semaines.The formulations were subjected to so-called "accelerated" stability tests, retaining them at 25 ° C or 40 ° C, for 6, 13 or 19 weeks.
La dégradation physique a été suivie, par analyse des phénomènes d'agrégation par HPSEC pour le suivi des dimères/oligomèes et polymères, la DLS (pour « dynamic light scattering », mesure de diffusion de la lumière) pour l'agrégation submicronique, le comptage de particules sub-visibles (taille entre 10 et 50µm), et observation visuelle (taille >50µm).The physical degradation was followed, by analysis of aggregation phenomena by HPSEC for the monitoring of dimers / oligomers and polymers, the DLS (for "dynamic light scattering", measurement of light scattering) for submicron aggregation, the counting of sub-visible particles (size between 10 and 50μm), and visual observation (size> 50μm).
La stabilité chimique a été suivie par HPSEC et SDS-PAGE pour suivre la fragmentation, et le dosage des anti-HBs (anticorps anti-antigènes de surface de l'hépatite B) a fourni un indicateur de la stabilité de la fonction Fab.Chemical stability was followed by HPSEC and SDS-PAGE to track fragmentation, and assay for anti-HBs (hepatitis B surface antigen antibodies) provided an indicator of the stability of Fab function.
L'activité anti-complémentaire (AAC) a été déterminée, par mesure de la captation aspécifique du complément par les Ig. Ce test décrit l'aptitude des immunoglobulines à activer le système du complément, une activation trop puissante du complément pouvant nuire à la tolérance du produit lors de son injection.Anti-complementary activity (AAC) was determined by measuring the aspecific uptake of complement by Ig. This test describes the ability of immunoglobulins to activate the complement system, too strong activation of the complement may affect the tolerance of the product during its injection.
Les formulations IgNG, GT80 et GT20 ont globalement donné les meilleurs résultats.The IgNG, GT80 and GT20 formulations generally gave the best results.
Le tensioactif (Tween) a favorisé la stabilité physique des formulations.The surfactant (Tween) promoted the physical stability of the formulations.
De manière surprenante, la présence de mannitol ne s'est pas avérée essentielle, les formulations GT80 et GT20 (dépourvues de mannitol) présentant des stabilités au moins aussi bonnes que la formulation IgNG (avec mannitol).Surprisingly, the presence of mannitol was not essential, the GT80 and GT20 formulations (lacking mannitol) having stabilities at least as good as the formulation IgNG (with mannitol).
Les formulations suivantes sont donc retenues comme les plus avantageuses :
- Formulation GT80: Glycine 250mM,
Tween® 80 50ppm, pH =4,6 - Formulation GT20: Glycine 250mM,
Tween® 20 20ppm, pH=4,6
- Formulation GT80: Glycine 250mM,
Tween® 80 50ppm, pH = 4.6 - GT20 formulation: Glycine 250mM,
Tween® 20 20ppm, pH = 4.6
La stabilité de la formulation GT80 est comparée à celle d'une formulation IgNG, pendant 12 mois à 25°C et à 40°C.
A T0, les flacons sont placés dans des armoires thermostatées à 25°C et 40°C, et leur stabilité selon le protocole de stabilité accélérée est suivie selon l'échéancier suivant :
Après 12 mois à 25°C et 40°C, les formulations GT80 et IgNG présentent une stabilité comparable :
- Les formulations mises en stabilité ont des comportements identiques du point de vue de la dégradation chimique : la fragmentation est observée à 40°C par HPSEC et SDS-PAGE et une perte de l'activité Fab à 40°C ;
- Les formulations sont identiques en ce qui concerne l'agrégation submicronique observée à 40°C en DLS et en HPSEC ;
- Une agrégation macroscopique est observée à 40°C ainsi que l'apparition d'une coloration jaune. Cette coloration est identique pour les formulations GT80 et IgNG. A 25°C, les 2 formulations sont incolores.
- Les écarts observés en AAC restent faibles. Les deux formulations évoluent de façon comparable à 25°C et 40°C. Le mannitol ne contribue pas à la stabilité d'IgNG vis-à-vis du test AAC.
- Stability formulations have identical behavior from the point of view of chemical degradation: fragmentation is observed at 40 ° C by HPSEC and SDS-PAGE and loss of Fab activity at 40 ° C;
- The formulations are identical with respect to submicron aggregation observed at 40 ° C in DLS and HPSEC;
- Macroscopic aggregation is observed at 40 ° C and the appearance of a yellow color. This staining is identical for the GT80 and IgNG formulations. At 25 ° C, both formulations are colorless.
- The observed differences in AAC remain low. Both formulations evolve similarly at 25 ° C and 40 ° C. Mannitol does not contribute to the stability of IgNG with respect to the AAC test.
Ces résultats de stabilité à 12 mois confirment que l'adjonction de Mannitol est sans effet sur la stabilité d'IgNG.These 12-month stability results confirm that the addition of Mannitol has no effect on the stability of IgNG.
En définitive, la formulation GT80 constituée de Glycine (250 mM) et de Tween 80 (50 ppm) est une formulation stable adaptée à une utilisation thérapeutique commerciale. Après 12 mois à 25°C, toutes les analyses réalisées sont conformes selon la Pharmacopée Européenne.Ultimately, the GT80 formulation consisting of Glycine (250 mM) and Tween 80 (50 ppm) is a stable formulation suitable for commercial therapeutic use. After 12 months at 25 ° C, all the analyzes performed are according to the European Pharmacopoeia.
Claims (6)
- Liquid pharmaceutical composition which comprises 100 g/l of human immunoglobulins G (IgG), 250 mM of glycine, and 50 mg/l of Polysorbate 80, said composition having a pH between 4.4 and 4.8, and does not contain mannitol.
- Pharmaceutical composition according to claim 1, said composition having a pH of 4.6.
- Composition according to one of claims 1 to 2, characterized in that the only excipients are glycine and the non-ionic detergent.
- Composition according to one of claims 1 to 3, characterized in that the immunoglobulins G are obtained by fractionation of human blood plasma.
- Composition according to one of claims 1 to 4 which is obtained by reconstitution with water, from a lyophilizate.
- Solid composition obtained by desiccation, preferably freeze-drying, of a liquid composition according to one of claims 1 to 5.
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FR1054721A FR2961107B1 (en) | 2010-06-15 | 2010-06-15 | HUMAN IMMUNOGLOBULIN COMPOSITION STABILIZED |
PCT/FR2011/051358 WO2011157950A1 (en) | 2010-06-15 | 2011-06-15 | Stabilised human immunoglobulin composition |
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US20140186361A1 (en) | 2012-09-07 | 2014-07-03 | Coherus Biosciences, Inc. | Stable Aqueous Formulations of Adalimumab |
FR2977893B1 (en) | 2011-07-11 | 2015-02-20 | Lab Francais Du Fractionnement | PROCESS FOR PREPARING A CONCENTRATE OF MULTIPURPOSE IMMUNOGLOBULINS |
US11229702B1 (en) | 2015-10-28 | 2022-01-25 | Coherus Biosciences, Inc. | High concentration formulations of adalimumab |
FR3045387A1 (en) * | 2015-12-18 | 2017-06-23 | Lab Francais Du Fractionnement | COMPOSITION OF HUMAN CONCENTRATED IMMUNOGLOBULINS |
WO2017184880A1 (en) | 2016-04-20 | 2017-10-26 | Coherus Biosciences, Inc. | A method of filling a container with no headspace |
FR3081328B1 (en) * | 2018-05-24 | 2021-01-01 | Lab Francais Du Fractionnement | COMPOSITION OF CONCENTRATED HUMAN IMMUNOGLOBULINS |
MX2021012710A (en) * | 2019-04-18 | 2021-11-12 | Momenta Pharmaceuticals Inc | Sialylated glycoproteins. |
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WO1995003826A1 (en) * | 1993-07-30 | 1995-02-09 | Pasteur Merieux Sérums Et Vaccins | Stabilised immunoglobulin preparations and method for preparing same |
WO2005073252A1 (en) * | 2004-01-30 | 2005-08-11 | Suomen Punainen Risti Veripalvelu | Process for the manufacture of virus safe immunoglobulin |
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JPH0825902B2 (en) * | 1985-02-21 | 1996-03-13 | 株式会社ミドリ十字 | Method for heat treatment of γ-globulin |
US5945098A (en) * | 1990-02-01 | 1999-08-31 | Baxter International Inc. | Stable intravenously-administrable immune globulin preparation |
SE501476C2 (en) | 1992-10-21 | 1995-02-27 | Nilsson Carl O Lennart | Cylinder bolt mechanism at repeater rifle |
GB9418092D0 (en) * | 1994-09-08 | 1994-10-26 | Red Cross Found Cent Lab Blood | Organic compounds |
EP0973549A2 (en) * | 1997-04-07 | 2000-01-26 | Cangene Corporation | Intravenous immune globulin formulation containing a non-ionic surface active agent with improved pharmacokinetic properties |
FR2824568B1 (en) | 2001-05-11 | 2004-04-09 | Lab Francais Du Fractionnement | PROCESS FOR THE PREPARATION OF HUMAN IMMUNOGLOBULIN CONCENTRATES FOR THERAPEUTIC USE |
PT1441589E (en) * | 2001-11-08 | 2012-08-13 | Abbott Biotherapeutics Corp | Stable liquid pharmaceutical formulation of igg antibodies |
FR2853551B1 (en) * | 2003-04-09 | 2006-08-04 | Lab Francais Du Fractionnement | STABILIZING FORMULATION FOR IMMUNOGLOBULIN G COMPOSITIONS IN LIQUID FORM AND LYOPHILIZED FORM |
EP1532983A1 (en) | 2003-11-18 | 2005-05-25 | ZLB Bioplasma AG | Immunoglobulin preparations having increased stability |
FR2895263B1 (en) * | 2005-12-26 | 2008-05-30 | Lab Francais Du Fractionnement | CONCENTRATE OF IMMUNOGLOBIN G (LG) DEPLETED ANTI-A AND ANTI-B ANTIBODIES, AND POLYREACTIVE IGG |
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2010
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- 2011-06-15 BR BR112012032215A patent/BR112012032215A2/en not_active Application Discontinuation
- 2011-06-15 CN CN2011800296486A patent/CN103025355A/en active Pending
- 2011-06-15 WO PCT/FR2011/051358 patent/WO2011157950A1/en active Application Filing
- 2011-06-15 CN CN201510628079.7A patent/CN105381465A/en active Pending
- 2011-06-15 ES ES11735499T patent/ES2762181T3/en active Active
- 2011-06-15 US US13/704,375 patent/US20130216522A1/en not_active Abandoned
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- 2011-06-15 KR KR1020137000980A patent/KR20130119904A/en not_active Application Discontinuation
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WO1995003826A1 (en) * | 1993-07-30 | 1995-02-09 | Pasteur Merieux Sérums Et Vaccins | Stabilised immunoglobulin preparations and method for preparing same |
WO2005073252A1 (en) * | 2004-01-30 | 2005-08-11 | Suomen Punainen Risti Veripalvelu | Process for the manufacture of virus safe immunoglobulin |
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CN103025355A (en) | 2013-04-03 |
CA2800757A1 (en) | 2011-12-22 |
CN105381465A (en) | 2016-03-09 |
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US20130216522A1 (en) | 2013-08-22 |
KR20170098323A (en) | 2017-08-29 |
BR112012032215A2 (en) | 2016-11-22 |
CA2800757C (en) | 2018-12-18 |
AR081928A1 (en) | 2012-10-31 |
AU2011266878B2 (en) | 2015-01-22 |
WO2011157950A1 (en) | 2011-12-22 |
EP2582394A1 (en) | 2013-04-24 |
JP2013528637A (en) | 2013-07-11 |
ES2762181T3 (en) | 2020-05-22 |
AU2011266878A1 (en) | 2012-12-13 |
JP2016138135A (en) | 2016-08-04 |
FR2961107A1 (en) | 2011-12-16 |
IL223292A0 (en) | 2013-02-03 |
IL223292A (en) | 2016-12-29 |
KR20130119904A (en) | 2013-11-01 |
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